Resistance of tumor cells to cancer therapy, limited efficacy of cancer therapy in metastatic disease, and undesired host toxicity of cancer therapy are three significant challenges in patient management.
A common resistance mechanism to chemotherapy observed in preclinical studies is the overexpression of drug efflux proteins (Lum, B. L. et al. (1993) Cancer 72, 3502-3514; Barrand, M. A. et al. (1997) Gen. Pharmacol. 28, 639-645; Fidler, I. J. (1999) Cancer Chemother. Pharmacol. 43:S3-S10.). However, at least some clinical studies show that inhibition of the drug efflux proteins does not significantly improve the effectiveness of chemotherapy in patients (Ferry, D. R., et al. (1996) Eur. J. Cancer 32:1070-1081; Broxterman, H. J., et al. (1996) Eur. J. Cancer. 32:1024-1033), suggesting the existence of other resistance mechanisms.
Cancer therapy, such as chemotherapy and radiation, targets proliferating cells and thereby causes undesired toxicity to normal host tissues that undergo continuous renewal, including the hematopoietic cells, cells in the lining of the gastrointestinal tract, and hair follicles. Bone marrow suppression induced by cancer therapy is, at least in part, overcome by the use of hematopoietic growth factors, including erythropoietin, granulocytes colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor (Gabrilove, J. L. and Goldie, D. W. (1993) In: Cancer, Principles and Practice of Oncology (eds. DeVita, V. T. et al., J. B. Lippincott Co., Philadelphia). On the other hand, no treatment is available to overcome the gastrointestinal toxicity and alopecia induced by anticancer agents.
Therefore, there exists a need to identify new mechanisms by which tumor and normal cells elude cytotoxicity of anticancer agents, to identify methods and agents to overcome such resistance in tumor cells, and to utilize these resistance mechanisms to protect normal host tissues from the undesired toxicity of cancer therapy.
The invention is based, at least in part, on the elucidation of the role played by basic Fibroblast Growth Factor (bFGF) in the induction of broad spectrum resistance to anticancer agents in a number of tumors and metastatic lesions, and the role played by acidic FGF (aFGF) in amplifying the bFGF-induced resistance. Inhibitors of aFGF/bFGF enhance the in vitro and in vivo activity of anticancer agents, and result in shrinkage and eradication of human xenograft tumors including lung metastasis and subcutaneous tumors in mice. Methods of the invention use FGF antagonists to potentiate the antitumor effect of anticancer agents. FGF agonists (e.g., aFGF, e.g., bFGF) reduce the cytotoxicity of anticancer agents to normal noncancerous intestinal epithelial cells. Methods of the invention use FGF agonists to protect normal cells from the cytotoxic effects of anticancer agents.
Accordingly, in general, the invention features, a method of inhibiting unwanted cell growth or division, e.g., reducing or inhibiting the proliferation of, or enhancing the killing of, a cell, e.g., a hyperproliferative cell, e.g., a malignant cell or a benign hyperproliferative cell. The method includes: contacting the cell with at least one cytotoxic agent, (e.g., a cytostatic agent, e.g., an agent that causes cell death) and at least one FGF antagonist, in an amount, which together, is effective to reduce or inhibit the proliferation of the cell, or induce cell killing. Preferably, the unwanted cell is the cell of an established tumor.
In another aspect, the invention features a method of improving the efficacy of an agent, e.g., a cytotoxic agent, in a subject. The method includes:
administering to the subject at least one agent, e.g., a cytotoxic agent;
administering to the subject at least one FGF antagonist.
The FGF antagonist enhances the efficacy of the agent, e.g., a cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist.
In a preferred embodiment, the FGF antagonist improves the efficacy of the cytotoxic agent against a cancer, e.g., an established tumor.
In another aspect, the invention features, a method of inhibiting unwanted cell growth or division, or inducing the killing of an unwanted cell (e.g., a hyperproliferative cell), e.g., a cell of an established tumor or a benign hyperproliferative cell, in a subject. The method can be used to treat or prevent, in a subject, a disorder characterized by unwanted cell growth or division. The method includes: administering to the subject at least one cytotoxic agent, (e.g., a cytostatic agent, an agent that causes cell death), and at least one FGF antagonist, in an amount, which together, is effective (e.g., therapeutically or prophylactically) to reduce or inhibit the growth or division of, or induce the killing of, the unwanted cell. Preferably, the unwanted cell is the cell of an established tumor.
In a preferred embodiment, the FGF antagonists inhibits or reduces the FGF-induced resistance to a broad spectrum of cytotoxic agents, i.e., agents with diverse structures and mechanisms of action, including but not limited to, antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway (e.g., protein kinase C inhibitors, e.g., anti-hormones, e.g., antibodies against growth factor receptors), agents that promote apoptosis and/or necrosis, interferons, interleukins, tumor necrosis factors, and radiation.
In a preferred embodiment, the FGF antagonist comprises an inhibitor of bFGF.
In a preferred embodiment, the FGF antagonist comprises an inhibitor of aFGF.
In a preferred embodiment, the FGF antagonist includes at least one bFGF inhibitor and at least one aFGF inhibitor.
In a preferred embodiment, the aFGF inhibitor potentiates the action of the bFGF inhibitor.
In a preferred embodiment, the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to its receptor.
In a preferred embodiment, the FGF antagonist acts intracellularly, e.g., interacts with the intracellular domain of the FGF receptor, inhibits the intracellular effects of FGF.
In a preferred embodiment, the FGF antagonist: is capable of binding to an FGF molecule or an FGF receptor; blocks the binding of FGF to a receptor; blocks the interaction of FGF with molecules that facilitate the binding of FGF to a receptor; and/or down regulates FGF receptor action. Preferably, the FGF molecule is bFGF and/or aFGF.
In a preferred embodiment, the FGF antagonist is other than suramin.
In a preferred embodiment, the FGF antagonist is other than an antibody, e.g., an antibody against FGF or an FGF receptor.
In a preferred embodiment, the FGF antagonist inhibits or reverses the resistance to anticancer drugs induced by FGF (e.g. aFGF and/or bFGF) or conditioned medium of tumor histocultures in cultured tumor cells under in vitro conditions as described in Example II and Example IV. The determination of effect on cultured cells can be determined using the system described in Example XV.
In a preferred embodiment, the FGF antagonist improves the efficacy of an agent, e.g., a cytotoxic agent, in the subject, relative to the effect of the cytotoxic agent in the absence of the FGF antagonist. Preferably, the FGF antagonist improves the efficacy of the cytotoxic agent against an established tumor.
In a preferred embodiment, the FGF antagonist is present in an amount sufficient to block FGF (e.g., bFGF and/or aFGF) action, but is not sufficient to cause one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject; and/or (iv) significant cell cycle arrest. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the FGF antagonist is administered at levels such that the plasma concentration of the FGF antagonist that is present when the cytotoxic agent is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that if the same concentration of FGF antagonist is provided in cultured cells at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, and most preferably at least 99% of the treated cultured cells continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with the FGF antagonist. The determination of effect on cultured cells should be determined with the system described in Example XV.
In a preferred embodiment, the FGF antagonist is administered at levels that, although not resulting in significant cell cycle arrest, significant cell death, or significant inhibition of cell growth as described above, sensitizes the tumor cells to treatment with cytotoxic agents. Preferably the levels of FGF antagonist result in a significant inhibition of FGF-mediated chemoresistance, e.g., the resistance of tumor cells to cytotoxic agents that is mediated by FGF. Preferably the FGF antagonist inhibits at least 10, more preferably, at least 25, more preferably at least, 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, and most preferably at least 99% of the FGF-mediated chemoresistance. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent, is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
In a preferred embodiment, the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
In a preferred embodiment, the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the time period over which the FGF antagonist is administered or over which the FGF antagonist is maintained at a therapeutic level, e.g., at a plasma concentration that is sufficient to enhance the cytotoxic effect of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the FGF antagonist: is a protein or a peptide; is an antibody, e.g., a monoclonal, a murine antibody or a human antibody, or an antigen-binding fragment thereof. Preferably, the monoclonal antibody is a human antibody. The antibodies can be of the various isotypes, including: IgG (e.g., IgG1, IgG2, IgG3, IgG4), IgM, IgA1, IgA2, IgD, or IgE. Preferably, the antibody is an IgG isotype. The antibodies can be full-length (e.g., an IgG1 or IgG4 antibody) or can include only an antigen-binding fragment (e.g., a Fab, F(abxe2x80x2)2, Fv or a single chain Fv fragment).
In a preferred embodiment, the FGF antagonist: is a recombinant antibody, e.g., a chimeric or a humanized antibody, or an antigen binding fragment thereof, e.g., has a variable region, or at least a complementarity determining region (CDR), derived from a non-human antibody (e.g., murine), while the remaining portion(s) are human in origin.
In a preferred embodiment, the FGF antagonist is a fragment of the FGF molecule. Preferably, the FGF fragment competes with an FGF molecule for binding to the receptor.
In a preferred embodiment, the FGF antagonist is a small molecule, (e.g., is selected from a combinatorial library).
In a preferred embodiment, the FGF antagonist is chosen from those disclosed herein, e.g., suramin, structural analogs of suramin, anti-FGF antibodies, anti-FGF receptor antibodies, pentosan polysulfate, scopolamine, angiostatin, sprouty, estradiol, carboxymethylbenzylamine dextran (CMDB7), suradista, insulin-like growth factor binding protein-3, ethanol, heparin (e.g., 6-O-desulfated heparin), low molecular weight heparin, heparan sulfate, protamine sulfate, transforming growth factor beta, cyclosporin A, or RNA ligands for bFGF.
In a preferred embodiment, the FGF antagonist is heparin.
In a preferred embodiment, the FGF antagonist is low molecular weight heparin.
In a preferred embodiment, the FGF antagonist is heparan sulfate.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody.
In a preferred embodiment, the FGF antagonist is suramin.
In a preferred embodiment, the FGF antagonist is suramin and the suramin is present in a concentration that is sufficient to block the resistance to anticancer agents induced by FGF (e.g., bFGF and/or aFGF), but is not sufficient to produce one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject, and/or (iv) cell cycle arrest. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the FGF antagonist is suramin and it is administered at levels such that the plasma concentration of suramin that is present when the cytotoxic agent is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that, if the same concentration of suramin is provided in cultured cells, at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, more preferably at least 99, and most preferably at least 99% of the treated cultured cells continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with suramin. The determination of effect on cultured cells can be determined with the system described in Example XV.
Preferably, suramin is administered in an amount that results in a concentration ranging from about 0.1 to 100 xcexcg/ml, preferably about 1 to 85 xcexcg/ml, more preferably, about 5 to 60 xcexcg/ml, even more preferably, about 10 to 50 xcexcg/ml, and most preferably, 15 to 45 xcexcg/ml. The pharmacokinetics of suramin is characterized by a triphasic concentration decline, with half-lives of 5.5 hours, 4.1 days and 78 days. The total body clearance is 0.0095 liter/hour/m2 (Jodrell et al (1994) J Clin Oncol 12:166-175). Based on pharmacokinetic principles, a person skilled in the art can calculate that an initial dose of approximately 240 mg/m2 should be administered to the average patient to achieve plasma concentrations declining from about 90 xcexcg/ml (63 xcexcM) to about 18 xcexcg/ml (13 xcexcM) over 96 hours. The 96 hour duration is chosen as an example, as the plasma concentrations of many commonly used cytotoxic agents to be administered with suramin will have declined below their therapeutic levels at 96 hours. Similar calculations can be performed to identify the initial suramin dose to deliver the preferred suramin plasma concentrations over other desired treatment durations. Maintenance doses to adjust the plasma concentrations for later treatment cycles can be similarly calculated.
In a preferred embodiment, the total suramin exposure is preferably less than 800 xcexcM-day over 96 hours, preferably less than 600 xcexcM-day over 96 hours, preferably less than 500 xcexcM-day over 96 hours, preferably less than 400 xcexcM-day over 96 hours, preferably less than 300 xcexcM-day over 96 hours, preferably less than 252 xcexcM-day over 96 hours, preferably less than 200 xcexcM-day over 96 hours, preferably less than 150 xcexcM-day over 96 hours, preferably less than 100 xcexcM-day over 96 hours, and most preferably less than 52 xcexcM-day over 96 hours. The total suramin exposure, as expressed in xcexcM-day, is a product of the drug plasma concentration in xcexcM-day (e.g., the average micromolarity over 24 hours) and the treatment duration in days. For example, treatment of a subject with 13 xcexcM of suramin for four days would result in a total drug exposure of 52 xcexcM-day over 96 hours.
Preferably, suramin is administered in an amount that results in a plasma concentration of less than 100, preferably less than 80, preferably less than 50, preferably less than 25, more preferably less than 15, and most preferably less than 10 xcexcM. Preferably, this plasma concentration is maintained for less than 20 days, preferably less than 15 days, preferably less than 12 days, preferably less than 10 days, more preferably less than 8 days, and most preferably less than 5 days beyond the time duration where therapeutic concentrations of a cytotoxic agent are maintained.
In a preferred embodiment the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
In a preferred embodiment, suramin is given immediately or within 3, 2, or 1 day before the administration of the cytotoxic agent, ending immediately after plasma concentrations of the cytotoxic agent are below the therapeutic level.
In a preferred embodiment, the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
In a preferred embodiment, the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the FGF antagonist is suramin and the time period over which the suramin is administered or over which the suramin is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
Methods described herein use suramin to enhance the antitumor effect of a cytotoxic agent (e.g., agents described in Table 2), where the suramin dose is selected to deliver a plasma concentration of below 100 xcexcg/ml, preferably below 75 xcexcg/ml, most preferably below 50 xcexcg/ml, in a mammal while the cytotoxic agent is present in plasma at a pharmacologically active concentration. The suramin dose is administered before, simultaneously with, or after the administration of the at least one anticancer agent. Animal trials presented herein show that treatment of mice with two weekly intravenous bolus suramin doses of 10 mg/kg for 3 weeks enhances the antitumor effect of anticancer drugs (e.g., paclitaxel, doxorubicin) but does not result in additional body weight loss. This dose is calculated to result in a plasma suramin concentration of about 10 xcexcM (xcx9c14 xcexcg/ml) at 72 hours after dose administration (see Example IX, Tables 4 and 5, FIG. 7). The methods of the art use high dose suramin, either alone or in combination with a cytotoxic agent, where for a human subject, maintenance of plasma suramin concentrations of between 150 to 300 xcexcg/ml is needed to produce a measurable antitumor effect (Eisenberger et al (1995) J Clin Oncol 13:2174-2186). A typical suramin dosing schedule aimed at maintaining suramin plasma concentrations between 150 and 300 xcexcg/ml consists of an initial administration of 2100 mg/m2 over the first week with the subsequent doses repeated every 28 days for 6 months or longer; the subsequent doses are adjusted using the Bayesian pharmacokinetic method (Dawson et al (1998) Clin Cancer Res 4:37-44, Falcone, et al (1999) Cancer 86:470-476). Moreover, the methods of the art for using suramin in combination with other cytotoxic agents often administer suramin at a more frequent schedule or a longer duration than the frequency and the treatment duration for the other cytotoxic agents. For example, in the combination of suramin and doxorubicin for the treatment of androgen-independent prostate cancer, the duration of doxorubicin treatment was up to 20 weeks whereas the duration of the suramin treatment was up to 45 weeks (Tu et al (1998) Clin Cancer Res 4:1193-1201). For example, in the combination of suramin and mitomycin C for the treatment of hormone-resistant prostate cancer, suramin was given weekly whereas mitomycin C was given only every 5 weeks (Rapoport et al (1993) Ann Oncol 4:567-573). At these doses and chronic treatments, suramin causes the following toxicity in a human patient: adrenal insufficiency, coagulopathy, peripheral neuropathy, and proximal muscle weakness (Dorr and Von Hoff, Cancer Chemotherapy Handbook, 1994, pp 859-866). The incidence and severity of these toxicities are positively related to cumulated dose and are minimized in the methods described herein.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody. Preferably, the anti-FGF antibody is present in a concentration that is sufficient to block the resistance to anticancer agents induced by FGF (e.g., bFGF and/or aFGF), but is not sufficient to produce one or more of: (i) significant inhibition of cell proliferation; (ii) significant cell death in human and/or animal tumor cells, (iii) a measurable antitumor effect in a subject, e.g., a human subject, and/or (iv) cell cycle arrest.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody and it is administered at levels such that the plasma concentration of the anti-FGF antibody that is present when the cytotoxic agents is present in plasma at pharmacologically active concentration does not result in one or more of: (i) significant cell cycle arrest, (ii) significant cell death, or (iii) significant inhibition of cell growth, e.g., the concentration in plasma is of a level that if the same concentration of the anti-FGF antibody is provided in cultured cells at least 10, more preferably at least 25, more preferably at least 50, more preferably at least 70, more preferably at least 80, more preferably at least 90, more preferably at least 99, and most preferably at least 99% of the treated cultured cells, continue to be involved in one or more of: (i) cycling cells continue to progress through the cell cycle, (ii) cells remain viable, or (iii) cells remain capable of proliferating, following treatment with the FGF antibody. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti-FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti-FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti-FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the FGF antagonist is an anti-FGF antibody and the time period over which the anti-FGF antibody is administered or over which the anti-FGF antibody is maintained at the plasma concentration sufficient to inhibit or reverse the FGF-mediated resistance or to enhance the efficacy of the cytotoxic agent begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the method inhibits the proliferation of, or enhances the killing of, a hyperproliferative cell selected from the group consisting of a solid tumor cell, a soft-tissue tumor cell, a metastatic tumor cell, a leukemic tumor cell, and a lymphoid tumor cell.
In a preferred embodiment, the method inhibits the proliferation of, or enhances the killing of, a hyperproliferative cell in a fibrotic tumor.
In a preferred embodiment, the disorder is a cancer, e.g., a sarcoma, a carcinoma, an adenocarcinoma, a lymphoma, or a leukemia.
In a preferred embodiment, the disorder is a cancer which includes an established tumor.
In a preferred embodiment, the disorder is a cancer which includes a solid tumor.
In a preferred embodiment, the disorder is a cancer which includes a metastatic lesion.
In a preferred embodiment, the disorder is a cancer which includes a leukemia.
In a preferred embodiment, the disorder is a cancer which includes a lymphoma.
In a preferred embodiment, the disorder is a cancer, e.g., a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing""s tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, oaoukkart carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm""s tumor, cervical cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medullobastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neurobastoma, retinoblastoma, leukemia, lymphoma, or Kaposi sarcoma.
In a preferred embodiment, the disorder includes a cancer which includes cells, e.g., tumor or metastatic cells, which form from a tissue where an FGF molecule is expressed, preferably at high levels, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
In a preferred embodiment, the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system..
In a preferred embodiment, the disorder is a cancer which includes an established tumor, e.g., a tumor that has been growing in a subject for at least one week, preferably two weeks, preferably one month, preferably two months, more preferably three months, more preferably six months, and most preferably longer than six months.
Preferably, an established tumor can be diagnosed clinically.
Preferably, an established tumor can be visualized on diagnostic media, e.g., an X-ray, a CAT scan, or MRI.
Preferably, an established tumor can be diagnosed by the detection of tumor markers, e.g., prostate specific antigen for prostate cancer, Her2/neu for certain breast cancers, CA125 for ovarian cancer, or genetic alterations.
Preferably, an established tumor can be diagnosed by the detection of pathological changes, e.g., blood in sputum for lung cancer, blood in feces in colon cancer, blood in urine for bladder cancer, a lump in breasts for breast cancer, pain, or headache.
Preferably, an established tumor can be diagnosed by biochemical analysis of a patient sample, e.g., a patient""s sputum, feces, urine, etc.
Preferably, an established tumor can be diagnosed by morphological analysis of cells derived from a subject, e.g., morphological abnormalities, abnormal nucleus-to-cytoplasmic ratios, abnormal tissue architecture, abnormal tissue organization, or abnormal tissue composition.
Preferably, an established tumor is one that is visible, palpable, or found during necropsy or autopsy.
In a preferred embodiment, the disorder includes a cancer, e.g., lung cancer, renal cancer, glioma, melanoma, or chemotherapy-refractory cancer, a metastatic cancer, which is chemoresistant, e.g., shows little or no significant response to chemotherapy.
In a preferred embodiment, the hyperproliferative cell is found in a benign lesion.
In a preferred embodiment, the disorder is selected from the group consisting of psoriasis, cysts, benign prostatic hyperplasia, and endometriosis.
In a preferred embodiment, the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn""s disease, hepatic adenoma, hepatic cirrhosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia, erythroplasia of the penis, polyps and papillomas of the vulva, vagina, or cervix, endometrial polyps, adenomas, papillomas, or leimyomas, ovarian cysts, fibrocystic disease of the breast, lipoma of the breast, sclerosing adenosis, hemangioma, ductal hyperplasia of the breast, fibroadenomas, adenomyoepitheliomas, hamartoma, nevus of the skin, genodermatoses, fibrosis of the bone, fibrous dysplasia, chondrodysplasisa, sclerosing bone dysplasia, axial osteomalacia, fibrogenesis imperfecta, osteomas, osteoid osteomas, osteoblastomas, osteochondomas, enchondromas, chondromyxoid fibromas, chondroblastomas, synovial lipomas, adenomas of endocrine organs, goiter, Graves"" disease, adrenal hyperplasia, adrenal adenomas, adrenal MEN I syndrome, adrenal myelolipomas.
In a preferred embodiment, the subject is a mammal, e.g., a human. E.g., the subject is a patient, e.g., a cancer patient. The subject can be a patient with non-small cell lung cancer, is treated with a combination of paclitaxel, carboplatin and an FGF antagonist, e.g., suramin, or with a combination of gemcitabine, cisplatin, and an FGF antagonist, e.g., suramin. The subject can be a patient with hormone refractory prostate cancer, who is treated with a combination of estramustine phosphate, taxotere and an FGF antagonist, e.g., suramin, or with a combination of doxorubicin, ketoconazole and an FGF antagonist, e.g., suramin. The subject can be a patient with metastatic breast cancer, who is treated with a combination of cyclophosphamide, doxorubicin, 5-fluorouracil and an FGF antagonist, e.g., suramin, or a combination of doxorubicin, taxotere and an FGF antagonist, e.g., suramin. The subject can be a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with a HER2/neu inhibitor (e.g., a HER2/neu antibody) and an FGF antagonist, e.g., suramin, with or without paclitaxel or cisplatin. The subject can be a patient with advanced or metastatic colorectal cancer, who is treated with a combination of irinotecan and an FGF antagonist, e.g., suramin. The subject can be a patient with advanced colon cancer, who is treated with a combination of 5-fluorouracil, leucovorin and an FGF antagonist, e.g., suramin.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitory, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate=PALA,N-Phosphoracetyl-L-Asparate (PALA), pentostatin, N-Phosphoracetyl-L-Asparate=PALA, pentostatin,5-azacitidine, 5-Aza-C, BCNU=Carmustine,5-azacitidine,5-Aza- 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU=Carmustine,BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, Lupron, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoledax), flutamide, 4xe2x80x2-cyano-3-(4-(e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-3-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (Docetaxel), topotecan, irinotecan hydrochloride=Camptosar, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate=PALA, pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin, mitomycin C, BCNU=Carmustine, melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, Lupron, ketoconazole, tamoxifen, goserelin (Zoledax), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere amsacrine, (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate=PALA, pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), idarubicin, teniposide, amsacrine, epirubicin, merebarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere(e.g., Docetaxel), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), b 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, taxotere, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is present in an amount equal to or lower than the one used in conventional chemotherapy. For example, for the combination of paclitaxel and carboplatin with an FGF antagonist, the dose of paclitaxel is equal to or below 225 mg/m2, and the dose of carboplatin is chosen to achieve a total concentration-time product of equal to or below 6-7 mg/ml.min in previously untreated patients, or equal to or below 4-5 mg/ml.min in patients that have received chemotherapy previously; the treatment is repeated every 3 weeks. For example, for the combination of estramustine phosphate and taxotere with an FGF antagonist, the daily oral dose of estramustine is equal to or below 1400 mg, and the dose of taxotere is equal to or below 70 mg/m2 over 1 hour; the treatment is repeated every 3 weeks. For example, for the combination of doxorubicin and ketoconazole with an FGF antagonist, the weekly dose of doxorubicin is equal to or below 20 mg/m2 by 24 hr infusion, and the total daily oral dose of ketoconazole is equal to or below 1200 mg. For example, for the combination of cyclophosphamide, doxorubicin and 5-fluorouracil with an FGF antagonist, the dose of intravenous cyclophosphamide is equal to or below 500 mg/m2, the dose of doxorubicin is equal to or below 50 mg/m2, and the dose of 5-fluorouracil is equal to or below 500 mg/m2; the treatment is repeated every 4 weeks (the 5-fluorouracil dose is given once per week for two weeks whereas the doses of doxorubicin and cyclophosphamide are given once every 4 weeks). For example, for the combination of Herceptin and cisplatin with an FGF antagonist, the Herceptin dose is equal to or below 250 mg on day 0, followed by 9 weekly doses of equal to or below 100 mg, and the cisplatin dose is equal to or below 75 mg/m2 on days 1, 29, and 57. For example, for the combination or irinotecan with an FGF antagonist, the four weekly doses of irinotecan are equal to or below 125 mg/m2; the treatment cycle is 4 weeks on and 2 weeks off. For example, for the combination of irinotecan with an FGF antagonist, the dose of irinotecan is 350 mg/m2 every 3 weeks. For example, for the combination of 5-fluorouracil and leucovorin with an FGF antagonist, the five daily intravenous bolus doses of 5-fluorouracil are equal to or below 425 mg/m2, and the five daily intravenous bolus doses of leucovorin are equal to or below 20 mg/m2; the treatment cycle is 1 week on and 4 weeks off. For example, for the combination of gemcitabine and cisplatin with an FGF antagonist, the three weekly doses of gemcitabine are equal to or below 1000 mg/m2, and the single cisplatin dose given on day 2 is equal to or below 100 mg/m2; the treatment is repeated every 4 weeks.
In a preferred embodiment, the method further includes repeated dosages of the same, or a different cytotoxic agent.
In a preferred embodiment, the method further includes repeated dosages of the same, or a different FGF antagonist.
In a preferred embodiment, the cytotoxic agent and the FGF antagonist are administered at the same time or in overlapping time periods; the agent and the FGF antagonist are administered at different times; the agent is administered first and the FGF antagonist is administered subsequently; the FGF antagonist is administered first and the agent is administered subsequently.
In a preferred embodiment, the cytotoxic agent is administered systemically or locally. For example, the agent can be administered parenterally (e.g., subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, intrathecally, etc.), intravesically (i.e., urinary bladder), intraprostatically, orally, nasally, rectally, topically, and/or transdermally.
In a preferred embodiment, the FGF antagonist is administered systemically or locally. For example, the FGF antagonist can be administered parenterally (e.g., subcutaneously, intravenously, intramuscularly, intraperitoneally, intradermally, intrathecally, etc.), intravesically (i.e., urinary bladder), intraprostatically, orally, nasally, rectally, topically, and/or transdermally.
In a preferred embodiment, the methods described herein further comprise monitoring the FGF levels (e.g., a-FGF and/or b-FGF) of a subject prior to or during treatment. Preferably, the amount of an FGF antagonist administered to the subject is determined based upon the levels of FGF present in the subject, e.g., low concentrations of FGF in the subject require decreased doses of the FGF antagonist to overcome the chemoresistance mediated by FGF.
In another aspect, the invention features, a method of treating a cell, e.g., inhibiting cell killing, or protecting the ability of a cell (e.g., a dividing cells, preferably, a rapidly dividing cell) to proliferate, e.g., a method of protecting a rapidly dividing cell, in a subject, from one or more of killing, inhibition of growth or division or other damage caused, e.g., by a cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death). The method includes: administering, to the subject, an effective amount of at least one FGF agonist, thereby treating the cell, e.g., protecting or reducing the damage to the dividing cell from said cytotoxic agent.
In a preferred embodiment, the cell is: a cell from a body surface or cavity, e.g., a cell of the gastrointestinal or esophageal tract; a hair follicle cell; a hematopoietic cell, e.g., a hematopoietic stem cell.
In a preferred embodiment, the cell is part of the lining of the gastrointestinal tract or the esophageal tract.
In a preferred embodiment, the method inhibits hair loss; inhibits weight loss; inhibits the loss of gastrointestinal function; inhibits the loss of hematopoiesis.
In a preferred embodiment, the method further includes administering at least one cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death), e.g., an antiproliferative agent, e.g., an anticancer drug, e.g. radiation, e.g., an interferon, e.g., an interleukin, e.g., a tumor necrosis factor, to said subject.
In a preferred embodiment the cytotoxic agent is other than radiation, e.g., is an administered compound.
In a preferred embodiment, the cytotoxic agent is a compound other than an antimetabolite.
In a preferred embodiment, the FGF agonist is administered orally, locally, e.g., topically, or ex vivo. For example, the FGF agonist can be applied topically to treat hair follicles. In other embodiments, the cell, e.g., a bone marrow cell, can be treated ex vivo.
In a preferred embodiment, the FGF agonist is administered locally to a site, e.g., gastrointestinal tract, bone marrow, or the skin.
In a preferred embodiment, the FGF agonist is directly injected into the bone marrow.
In a preferred embodiment, the FGF agonist is applied topically, e.g. externally to the scalp.
In a preferred embodiment, the application of the FGF agonist does not significantly result in absorption into systemic circulation, and/or does not significantly result in a blood or plasma concentration that is sufficient to increase the proliferation of a tumor cell in the subject.
In a preferred embodiment, the FGF agonist is administered to a subject by a method that does not result in significant systemic administration or significant systemic levels of the FGF agonist, e.g. does not result in an increase in FGF agonist blood levels that promotes the chemoresistance of the tumor. Systemic administration or levels of the FGF agonist can be evaluated by determining the level of the FGF agonist in the blood before and after its administration to a subject. These two levels can then be tested in vitro and compared for their effect on the antitumor effect mediated by a cytotoxic agent against tumor cells. Preferably the FGF agonist blood level after administration should increase the IC50 of the cytoxic agent by less than 30, preferably less than 20, preferably less than 10, preferably less than 5, and most preferably less than 1% as compared to the IC50 of the cytotoxic agent in the presence of the blood levels of the FGF agonist prior to administration of the FGF agonist to the subject. The determination of effect on cultured cells can be determined with the system described in Example XV.
In a preferred embodiment, the subject is a mammal, e.g., a human. E.g., the subject is a patient, e.g., a cancer patient. For example, the subject is a patient with non-small cell lung cancer, e.g., suramin, or with a combination of two or more of gemcitabine, cisplatin, or an FGF antagonist, e.g., suramin. For example, the patient is a patient with hormone refractory prostate cancer, who is treated with a combination of two or more of estramustine phosphate, taxotere, or an FGF antagonist, e.g., suramin, or with a combination of two or more of: doxorubicin, ketoconazole, an FGF antagonist, e.g., suramin. For example, the patient is a patient with metastatic breast cancer, who is treated with a combination of two or more of cyclophosphamide, doxorubicin, 5-fluorouracil, or an FGF antagonist, e.g., suramin. For example, the patient is a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with Herceptin and suramin, with or without paclitaxel or cisplatin. For example, the patient is a patient with advanced or metastatic colorectal cancer, who is treated with one or more of: irinotecan or an FGF antagonist, e.g., suramin. For example, the patient is a patient with advanced colon cancer, who is treated with a combination of two or more of 5-fluorouracil, leucovorin, or an FGF antagonist, e.g., suramin.
In a preferred embodiment, the treatment protects said cell from an effect, e.g., a cytotoxic effect (e.g., cytostasis, e.g., cell kill, e.g., hair loss), of said cytotoxic treatment.
In a preferred embodiment, the FGF agonist comprises bFGF, aFGF, or bFGF and aFGF, or a fragment or an analog thereof When bFGF and aFGF are given in combination, they may have an additive effect, preferably, a synergistic effect. The FGF agonist is administered in an amount that results in concentrations sufficient to protect said cell from an effect, e.g., a cytotoxic effect (e.g., cytostasis, e.g., cell kill, e.g., hair loss), of said cytotoxic treatment. Administration of the FGF agonist may be repeated to provide protection throughout the duration of said cytotoxic treatment and/or throughout the duration when the plasma concentrations of the cytotoxic agent remain sufficient to produce a cytotoxic effect.
In a preferred embodiment, the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level, e.g., a plasma concentration that is sufficient to protect cells from the cytotoxic effects of the cytotoxic agent, is less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days.
In a preferred embodiment, the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level, e.g., a plasma concentration that is sufficient to protect cells from the cytotoxic effects of the cytotoxic agent, does not begin substantially earlier or end substantial later than the period over which the cytotoxic agent is administered or over which the cytotoxic agent is maintained at a therapeutic level.
In a preferred embodiment, the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level, e.g., plasma concentration that is sufficient to protect cells from the cytotoxic effects of the cytotoxic agent, ends less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days after the last day on which the cytotoxic agent is administered or the last day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the time period over which the FGF agonist is administered or over which the FGF agonist is maintained at a therapeutic level, e.g., a plasma concentration that is sufficient to protect cells from the cytotoxic effects of the cytotoxic agent, begins less than 180, more preferably less than 90, more preferably less than 60, and most preferably less than 30 days before the first day on which the cytotoxic agent is administered or the first day on which the cytotoxic agent is present at therapeutic levels.
In a preferred embodiment, the FGF agonist: is a peptide, or a small molecule.
In a preferred embodiment, the FGF agonist is nonproteinaceous.
In a preferred embodiment, the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent used in the methods described herein is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, and a tumor necrosis factor.
In a preferred embodiment, the cytotoxic agent used in the methods described herein is selected from the group consisiting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor.
In a preferred embodiment, the cytotoxic agent used in the methods described herein, is chosen from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, florafur, UFT (combination of uracil and florafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her 2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent used in the methods described herein, is chosen from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), pyrazofurin, doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate=PALA, Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her 2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and tumor necrosis factors.
In a preferred embodiment, the cytotoxic agent used in the methods described herein, is chosen from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, florafur, UFT (combination of uracil and florafur), 5-fluoro-2xe2x80x2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorourdine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her 2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent used in the methods described herein, is chosen from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her 2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent used in the methods described herein, is chosen from those, disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her 2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and tumor necrosis factors.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluororuacil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (Lupron) and flutamide.
In another aspect, the invention features, a pharmaceutical composition which includes at least one FGF antagonist, at least one cytotoxic agent (e.g., a cytostatic agent, e.g., an agent that causes cell death), and a pharmaceutically acceptable carrier, wherein said FGF antagonist is present in an amount effective to enhance the efficacy of the cytotoxic agent, in reducing or inhibiting the proliferation, or in enhancing the killing, of a hyperproliferative cell.
In a preferred embodiment, the pharmaceutical composition is packaged with directions to practice the methods described herein.
In a preferred embodiment, the pharmaceutical composition includes: an inhibitor of bFGF; an inhibitor of aFGF: or a bFGF inhibitor and an aFGF inhibitor.
In a preferred embodiment, the FGF antagonist inhibits or reverses the resistance to anticancer drugs induced by FGF (e.g. aFGF and/or bFGF) or conditioned medium of tumor histocultures in cultured tumor cells under in vitro conditions as described in Example II and Example IV. The determination of effect on cultured cells can be determined using the system described in Example XV.
In a preferred embodiment, the FGF antagonist inhibits or reduces the resistance of tumor cells to a broad spectrum of cytotoxic agents.
In a preferred embodiment, the FGF antagonist: is capable of binding to an FGF molecule or an FGF receptor; blocks the binding of FGF to a receptor; blocks the interaction of FGF to molecules that facilitate the binding of FGF to a receptor; down regulates FGF receptor action; is a protein or a peptide; is an antibody, e.g., a monoclonal, diabody, a murine antibody, a human antibody, a humanized or a chimeric antibody, or an antigen-binding fragment thereof, e.g., an Fab, F(abxe2x80x2)2, Fv or a single chain Fv fragment; is a truncated FGF molecule, or a fragment thereof.
In a preferred embodiment, the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to the extracellular domain of the FGF receptors.
In a preferred embodiment, the FGF antagonist acts intracellularly, e.g., inhibits the binding of an FGF molecule to the intracellular domain of the FGF receptors.
In a preferred embodiment, the FGF antagonist acts intracellularly, e.g., inhibits the intracellular effects of FGF.
In a preferred embodiment, the FGF antagonist acts extracellularly, e.g., inhibits the binding of an FGF molecule to its receptor.
In a preferred embodiment, the FGF antagonist is chosen from those disclosed herein, e.g., suramin, structural analogs of suramin, anti-FGF antibodies, anti-FGF receptor antibodies, pentosan polysulfate, scopolamine, angiostatin, sprouty, estradiol, carboxymethylbenzylamine dextran (CMDB7), suradista, insulin-like growth factor binding protein-3, ethanol, heparin (e.g., 6-O-desulfated heparin), low molecular weight heparin, heparan sulfate, protamine sulfate, transforming growth factor beta, cyclosporin A, or RNA ligands for bFGF.
In a preferred embodiment, the FGF antagonist is suramin.
In a preferred embodiment, the FGF antagonist is a fragment of the FGF molecule which competes with an FGF molecule for binding to the receptor; the FGF antagonist is a small molecule.
In a preferred embodiment, the FGF antagonist is a small molecule, is chosen from a combinatorial library.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation,
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interferon, an interleukin, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, a tumor necrosis factor, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a mitotic inhibitor, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an interleukin, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuidine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and florafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorourdine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C) trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, irinotecan hydrochloride (e.g., Camptosar), etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, carboplatin, oxaliplatin mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorourdine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone,, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-HER2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), camptothecin, topotecan, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-A), cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is selected from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (e.g., Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, and radiation.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, and-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, gemcitabine, fludarabine, irinotecan, taxotere, tamoxifen, goserelin, ketoconazole, anti-Her2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (e.g., Lupron) and flutamide.
In a preferred embodiment, the cytotoxic agent is present at an amount equal to or lower than the one used in conventional chemotherapy.
In a preferred embodiment, the hyperproliferative cell is a cancer cell.
In a preferred embodiment, the hyperproliferative cell is found in a benign lesion.
In a preferred embodiment, the disorder is selected from the group consisting of psoriasis, cysts, benign prostatic hyperplasia, and endometriosis.
In a preferred embodiment, the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn""s disease, hepatic adenoma, hepatic cirrhosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia, erythroplasia of the penis, polyps and papillomas of the vulva, vagina, or cervix, endometrial polyps, adenomas, papillomas, or leimyomas, ovarian cysts, fibrocystic disease of the breast, lipoma of the breast, sclerosing adenosis, hemangioma, ductal hyperplasia of the breast, fibroadenomas, adenomyoepitheliomas, hamartoma, news of the skin, genodermatoses, fibrosis of the bone, fibrous dysplasia, chondrodysplasisa, sclerosing bone dysplasia, axial osteomalacia, fibrogenesis imperfecta, osteomas, osteoid osteomas, osteoblastomas, osteochondomas, enchondromas, chondromyxoid fibromas, chondroblastomas, synovial lipomas, adenomas of endocrine organs, goiter, Graves"" disease, adrenal hyperplasia, adrenal adenomas, adrenal MEN I syndrome, adrenal myelolipomas.
In another aspect, the invention features, a pharmaceutical composition which includes at least one FGF agonist, and a pharmaceutically acceptable carrier, wherein said FGF agonist is present in an amount effective to protect, or reduce the damage, a cell, e.g., a rapidly dividing cell, from said cytotoxic agent.
In a preferred embodiment, the pharmaceutical composition is packaged with directions to practice the methods described herein.
In a preferred embodiment, the FGF agonist comprises bFGF; aFGF; or bFGF and aFGF, or a fragment or an analog thereof.
In a preferred embodiment, the FGF agonist comprises bFGF, or a fragment or an analog thereof.
In a preferred embodiment, the FGF agonist: is a peptide, or a small molecule.
In a preferred embodiment the FGF agonist is nonproteinaceous.
In a preferred embodiment, the cell is: a cell from a body surface or cavity, e.g., a cell of the gastrointestinal or esophageal tract; a hair follicle cell; a hematopoietic cell, e.g., a hematopoietic stem cell.
In a preferred embodiment, the cell is a part of the lining of the gastrointestinal tract or the esophageal tract.
In another aspect, the invention relates to kits for carrying out the combined administration of the FGF antagonist/agonist with other cytotoxic agents. In one embodiment, the kit comprises an FGF antagonist/agonist formulated in a pharmaceutical carrier, and at least one cytotoxic agent, formulated, as appropriate, in one or more separate pharmaceutical preparations.
In a preferred embodiment, the kit includes directions to practice the methods described herein.
In another aspect, the invention features a vaccine comprising an FGF polypeptide, or a FGF receptor-derived polypeptide, or a fragment of a proteoglycan that facilitates the binding of FGF to its receptors, and a pharmaceutically acceptable carrier, in an amount effective to immunize a subject against a neoplastic disease. The immunization against the neoplastic disease can be partial or complete. Said vaccine can be used to treat a cancer patient, or to prevent one or more of the occurrence of, recidivism of, and/or metastasis of, the neoplastic disease. For example, it could be administered to a patient who has had a tumor surgically removed, to prevent recurrence of the tumor.
In a preferred embodiment, the subject is a mammal, e.g., a human.
In a preferred embodiment, the subject is not a cancer patient.
In a preferred embodiment, the subject is a patient that is afflicted with an ailment caused by a benign hyperplasia of a normal tissue.
In a preferred embodiment, the subject is a patient, e.g., a cancer patient. For example, the subject can be a patient in remission, or a cancer patient undergoing treatment (e.g., conventional chemotherapy, alone or in combination, with the methods described herein). For example, the subject can be a patient with non-small cell lung cancer, treated with a combination of two or more of: paclitaxel, carboplatin or an FGF antagonist, e.g., suramin, or with a combination of two or more of: gemcitabine, cisplatin, or an FGF antagonist, e.g., suramin. The subject can be a patient with hormone refractory prostate cancer, who is treated with a combination of two or more of: estramustine phosphate, taxotere, or an FGF antagonist, e.g., suramin, or with a combination of two or more of: doxorubicin, ketoconazole, or an FGF antagonist, e.g., suramin. The subject can be a patient with metastatic breast cancer, who is treated with a combination of two or more of: cyclophosphamide, doxorubicin, 5-fluorouracil, or an FGF antagonist, e.g., suramin, or a combination of two or more of doxorubicin, taxotere, or an FGF antagonist, e.g., suramin. The subject can be a patient with advanced breast cancer that overexpresses the HER2/neu oncogene, who is treated with a HER2/neu inhibitor (e.g., a HER2/neu antibody) and/or an FGF antagonist, e.g., suramin, with or without paclitaxel or cisplatin. The subject can be a patient with advanced or metastatic colorectal cancer, who is treated with one or more of: irinotecan or an FGF antagonist, e.g., suramin. The subject can be a patient with advanced colon cancer, who is treated with a combination of two or more of: 5-fluorouracil, leucovorin, or an FGF antagonist, e.g., suramin. The subject can be a patient that is in remission but is with a cancer that has a good likelihood to recur, e.g., adult leukemia, e.g., early disseminated prostate cancer.
In another aspect, the invention features, a method for evaluating the effectiveness of a compound, e.g., for treating a disorder, e.g., a proliferative disorder, e.g., a malignant disorder, or for protecting cells, e.g., from a cytotoxic agent. The method includes:
contacting the compound with an FGF, e.g., aFGF or bFGF; and
evaluating the ability of the compound to inhibit or promote FGF activity,
inhibition being correlated with effectiveness of treating a disorder, and promotion being correlated with cell protection.
In a preferred embodiment, the method further comprises testing the compound to determine if it can modulate, e.g., increase, the efficacy of an agent which kills cells or inhibits cell growth, e.g., an anticancer agent. This can be done by administering the compound and the agent, together or separately, to a test cell or organism.
In a preferred embodiment, the method further comprises testing the compound to determine if it can modulate, e.g., increase, the efficacy of an agent which kills cells or inhibits cell growth, e.g., an anticancer agent, in the presence of FGF (e.g., bFGF, and/or aFGF) or conditioned medium of tumor histocultures. This can be done by administering the compound, the agent and the FGF, together or separately, to a test cell or organism.
In a preferred embodiment, the method further comprises testing the compound to determine if it can protect cells from an agent that kills cells or inhibits cell growth, e.g., a cytotoxic or an anticancer agent. This can be done by administering both the compound and the agent, together or separately, to a test cell or organism.
In a preferred embodiment the method includes:
providing a cell, e.g.. a cultured cell, a transformed cell, a cell from a cancer, or a test organism;
administering said compound to said cell (or test organism) and evaluating. FGF activity, cell proliferation, cell death, or tumor growth, e.g., metastatic tumor growth.
In a preferred embodiment, the disorder is a cancer which includes a sarcoma, a carcinoma, an adenocarcinoma, a lymphoma, or a leukemia.
In a preferred embodiment, the disorder is a cancer which includes a solid tumor.
In a preferred embodiment, the disorder is a cancer which includes a leukemia.
In a preferred embodiment, the disorder is a cancer which includes a lymphoma.
In a preferred embodiment, the disorder is a cancer which includes a metastatic lesion.
In a preferred embodiment, the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue where an FGF molecule is expressed, or cells that are in contact or exposed to aFGF, bFGF and/or FGF-producing cells or tissues.
In a preferred embodiment, the disorder includes a cancer which includes cells, e.g., metastatic cells, which form from a tissue of the breast, prostate, kidney, bladder, liver, lungs, lymph nodes, colon, rectum, skin, brain, pancreas, cervix, ovary, larynx, pharynx, oral mucosa, cancers of the head and neck, cancers of hematopoietic origin, or cancers of the lymphoid system.
In a preferred embodiment, the disorder is a cancer, e.g., a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing""s tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm""s tumor, cervical cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, or Kaposi sarcoma.
In a preferred embodiment, the disorder is selected from the group consisting of benign hyperplastic diseases, e.g., oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn""s disease, hepatic adenoma, hepatic cirrhosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia, erythroplasia of the penis, polyps and papillomas of the vulva, vagina, or cervix, endometrial polyps, adenomas, papillomas, or leimyomas, ovarian cysts, fibrocystic disease of the breast, lipoma of the breast, sclerosing adenosis, hemangioma, ductal hyperplasia of the breast, fibroadenomas, adenomyoepitheliomas, hamartoma, nevus of the skin, genodermatoses, fibrosis of the bone, fibrous dysplasia, chondrodysplasisa, sclerosing bone dysplasia, axial osteomalacia, fibrogenesis imperfecta, osteomas, osteoid osteomas, osteoblastomas, osteochondomas, enchondromas, chondromyxoid fibromas, chondroblastomas, synovial lipomas, adenomas of endocrine organs, goiter, Graves disease, adrenal hyperplasia, adrenal adenomas, adrenal MEN I syndrome, adrenal myelolipomas.
In a preferred embodiment, the compound is a protein or a peptide.
In a preferred embodiment, the compound is a chemical, e.g., a small molecule (e.g., a member of a combinatorial library).
In a preferred embodiment, the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway (e.g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, or radiation.
In a preferred embodiment, the cytotoxic agent is chosen from those disclosed below. Exemplary cytotoxic agents include: paclitaxel, vincristine, vinblastine, vindesine, vinorelbin, taxotere (e.g., Docetaxel), topotecan, camptothecin, irinotecan hydrochloride (e.g., Camptosar), doxorubicin, etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone, piroxantrone hydrochloride, 5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine (Ara-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate=PALA, N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine, 5-Aza-5-Aza-2xe2x80x2-deoxycytidine, adenosine arabinoside (Ara-cladribine, ftorafur, UFT (combination of uracil and ftorafur), 5-fluoro-2xe2x80x2-deoxyuridine, 5-fluorouridine, 5xe2x80x2-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU (e.g., Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine, geldenamycin, cytochalasins, depsipeptide, leuprolide (e.g., Lupron), ketoconazole, tamoxifen, goserelin (Zoladex), flutamide, 4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl) propionanilide, Herceptin, anti-CD20 (e.g., Rituxan), interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumor necrosis factors, and radiation.
In a preferred embodiment, the cytotoxic agent is: paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, a HER2/neu antibody (e.g., Herceptin), anti-CD20, leuprolide (Lupron) and flutamide.
In a preferred embodiment the cell is a rapidly dividing cell, a gastro intestinal cell, or a hair follicle cell, or a hematopoietic cell, e.g., a hematopoietic stem cell.
In another aspect, the invention features, a method of analyzing a sample, e.g., for the level of tumor resistance to anticancer agents. The method includes:
evaluating the level of one or more FGF genes or gene products, wherein an increase or decrease in the level of one or more FGF genes or gene products, relative to a control, indicates the presence of tumor resistance to anticancer agents.
In a preferred embodiment, the sample, e.g. a sample form a subject, is a sample of tissue having unwanted proliferation, e.g., a sample of a benign hyperplasic tissue, a sample from a primary tumor, a metastatic tumor, or a leukemia.
In a preferred embodiment, the expression of FGF genes or gene products is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application Ser. No. 60/137,345), and TFII-I.
In a preferred embodiment, the method is performed: on a sample from a mammal, a sample from a human subject; and a sample from a cancer patient; as part of therapeutic decision making; to determine if the individual from which the target FGF is taken should receive a drug or other treatment; to diagnose an individual for a disorder or for predisposition to resistance to treatment, to stage a disease or disorder.
In a preferred embodiment, the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, e.g. a particular FGF antagonist, or a dosage thereof, based on the level of FGF expression.
In some embodiments, nucleic acid (or protein) from the cell or sample is analyzed on positional arrays, e.g., DNA chip arrays. Accordingly, in preferred embodiments, the method further includes:
analyzing the sample by providing an array of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagent e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product;
hybridizing the sample with the array of capture probes, thereby analyzing the sample sequence.
In another aspect, the method includes a method of staging a disorder, e.g., a proliferative disorder, e.g., a benign hyperplastic disorder, e.g., a malignant disorder, in a subject. The method includes:
providing a sample, e.g., cancerous sample, e.g. a tissue, a bodily fluid, e.g., urine, blood, or CSF, a biopsy, from said subject;
evaluating the expression of one or more FGF genes, e.g., by contacting said cancerous sample with, a nucleic acid probe that selectively hybridizes to one or more FGF gene products;
wherein an increase in the level of said one or more FGF genes or gene products, relative to a control, indicates a stage in the disorder, e.g., the malignant disorder.
In a preferred embodiment the FGF genes or gene products are selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application Ser. No. 60/137,345), and TFII-I.
In preferred embodiments the method is performed: on a sample from a mammal, a sample from a human subject; e.g., a sample of a patient suffering from a benign hyperplastic disorder, e.g., a sample from a cancer patient; to determine if the individual from which the target nucleic acid or protein is taken should receive a drug or other treatment; to diagnose an individual for a disorder or for predisposition to resistance to treatment, to stage a disease or disorder.
In a preferred embodiment, the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, or a dosage thereof, based on the level of FGF expression.
In a preferred embodiment, the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element e.g., promoter.
In some embodiments, nucleic acid (or protein) from the cell or sample is analyzed on positional arrays, e.g., DNA-chip arrays. Accordingly, in preferred embodiments the method further includes:
analyzing the sample by providing an array of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagant, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product;
hybridizing the sample with the array of capture probes, thereby analyzing the sample sequence.
In another aspect, the invention features, a method of diagnosing a disorder, e.g., proliferative disorder, e.g., a malignant disorder, e.g., a benign hyperproliferative disorder, in a subject. The method includes:
providing a sample e.g., cancerous sample, e.g., a tissue, a bodily fluid (e.g., blood, urine, sputum, CSF), a biopsy, from said patient;
evaluating the expression of one or more FGF genes, e.g., by contacting said sample with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF genes products;
wherein an increase or decrease in the level of said one or more FGF genes or gene products, relative to a control, indicates the presence or absence of the disorder, e.g., the malignant disorder.
In a preferred embodiment, the FGF related genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
In a preferred embodiment, the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control of or an FGF gene control element, e.g., promoter.
In some embodiments, nucleic acid (or protein) from the cell or sample is analyzed on positional arrays, e.g., DNA-chip arrays. Accordingly, in preferred embodiments the method further includes:
analyzing the sample by providing an array of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product;
hybridizing the sample with the array of capture probes, thereby analyzing the sample sequence.
In other aspect, the invention features, a method for evaluating the efficacy of a treatment of a disorder, e.g., a proliferative disorder, e.g., a malignant disorder, in a patient, comprising:
providing a sample, e.g., a cancerous sample, e.g., a tissue, a bodily fluid (e.g., blood, urine, sputum, CSF), a biopsy, from said patient;
evaluating the expression of one or more FGF genes, e.g., by contacting said cancerous sample with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF gene products;
wherein a change, e.g., decrease, e.g., increase, in the level of said one or more FGF genes or gene products in a sample obtained after treatment, relative to the level of expression before treatment, is indicative of the efficacy of the treatment of said disorder.
In a preferred embodiment, the method further includes choosing a therapeutic modality, e.g., a particular anticancer treatment, or a dosage thereof, based on the level of FGF expression.
In a preferred embodiment the FGF genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
In a preferred embodiment, the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element, e.g., promoter.
In some embodiments, the nucleic acid (or protein) from the cell or sample is analyzed on positional arrays, e.g., DNA-chip arrays. Accordingly, in preferred embodiments the method further includes:
analyzing the sample by providing an array of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product;
hybridizing the sample with the array of capture probes, thereby analyzing the sample sequence.
In another aspect, the invention features, a method for evaluating the effectiveness of a treatment, e.g., the administration of a compound, for treating a disorder, e.g., a proliferative disorder, e.g., a malignant disorder. The method includes:
providing a cell, e.g., a cultured cell, a transformed cell, a cell from a cancer, or a test organism;
administering said treatment to said cell (or test organism) and evaluating the expression of one or more FGF genes, e.g., by contacting a sample from said cell (or test organism) with, a nucleic acid probe that selectively hybridizes to one or more FGF genes, or an antibody that specifically binds to one or more FGF gene products;
wherein a change, e.g., decrease, in the level of said one or more FGF genes or gene products in a sample given said treatment, e.g., relative to the level of expression without treatment, indicative of the effectiveness of the compound for treating said disorder.
In a preferred embodiment the FGF genes or gene product is selected from the group consisting of bFGF, aFGF, TSC22, VEGF, GAFA1, GAFA2, GAFA3 (originally designated as FSC1, FSC2, FSC3 in the U.S. Provisional Application No. 60/137,345), and TFII-I.
In a preferred embodiment the expression of an FGF gene is evaluated by evaluating the expression of a signal entity, e.g., a green fluorescent protein or other marker protein, which is under the control or an FGF gene control element, e.g., promoter.
In some embodiments, nucleic acid (or protein) from the cell or sample is analyzed on positional arrays, e.g., DNA-chip arrays. Accordingly, in preferred embodiments the method further includes:
analyzing the sample by providing an array of a plurality of capture probes, wherein each of the capture probes is positionally distinguishable from other capture probes of the plurality on the array, and wherein each positional distinguishable capture probe includes a unique reagent, e.g., an antibody or a nucleic acid probe which can identify an FGF gene or gene product;
hybridizing the sample with the array of capture probes, thereby analyzing the sample sequence.